Proprotein convertase subtilisin kexin type 9 (PCSK9) is a serine protease involved in regulating the levels of the low density lipoprotein receptor (LDLR) protein. Experiments have shown that adding PCSK9 to HepG2 cells lowers the levels of cell surface LDLR that increasing PCSK9 protein levels decreases levels of LDLR protein in the liver, and that PCSK9 knockout mice have increased levels of LDLR in the liver. PCSK9 has been shown to directly interact with the LDLR protein.
Various human PCSK9 mutations that result in either increased or decreased levels of plasma LDL-C have been identified. Several mutations in human PCSK9 cause gain-of-function effects in humans, including hypercholesterolemia, increased LDL-C cholesterol levels, and increased risk of coronary heart disease. Even rarer human PCSK9 mutations induce loss-of-function, resulting in lowered LDL-C levels and an 88% reduction in coronary heart disease risk.
Evidence demonstrates that PCSK9, in particular, lowers the amount of hepatic LDLR protein and thus compromises the liver's ability to remove LDL cholesterol from the circulation. The data indicates that PCSK9 action leads to increased LDL-C by lowering LDLR protein levels.
Accordingly, there is substantial evidence indicating that PCSK9 plays a role in the regulation of LDL; that the expression or upregulation of PCSK9 is associated with increased plasma levels of LDL cholesterol, that the corresponding inhibition or lack of expression of PCSK9 is associated with reduced LDL cholesterol plasma levels; and that decreased levels of LDL cholesterol have been found to confer protection against coronary heart disease.
Reductions in LDL cholesterol levels have been directly related to the rate of coronary events and moderate lifelong reduction in plasma LDL cholesterol levels has been found to correlate with a substantial reduction in the incidence of coronary events. Accordingly, there is great benefit to be reaped from the managed control of LDL cholesterol levels.
A need exists for the identification of agents that may be used to modulate cholesterol levels and block or inhibit or neutralize the activity of PCSK9. The present invention advances these interests by providing novel antagonists of PCSK9 for use for in blocking, inhibiting or neutralizing one or more of the activities of PCSK9 and/or in blocking the interaction of PCSK9 with LDLR and/or for the treatment of therapeutic conditions identified herein especially those involving or associated with high or aberrant lipid or cholesterol levels.